Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice

Background Alzheimer's Disease (AD) is a neurodegenerative disorder influenced by aging and genetic risk factors. The inheritance ofAPOE epsilon 4 and variants of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) are major genetic risk factors for AD. Recent studies showed that APOE binds to TREM2, thus raising the possibility of an APOE-TREM2 interaction that can modulate AD pathology. Methods The aim of this study was to investigate this interaction using complex AD model mice - a crossbreed of Trem2(ko)and APP/PSEN1dE9 mice expressing human APOE3 or APOE4 isoforms (APP/E3 and APP/E4 respectively), and their WT littermates (E3 and E4), and evaluate cognition, steady-state amyloid load, plaque compaction, plaque growth rate, glial response, and brain transcriptome. Results In both, APP/E3 and APP/E4 mice,Trem2deletion reduced plaque compaction but did not significantly affect steady-state plaque load. Importantly, the lack of TREM2 increased plaque growth that negatively correlated to the diminished microglia barrier, an effect most pronounced at earlier stages of amyloid deposition. We also found thatTrem2deficiency significantly decreased plaque-associated APOE protein in APP/E4 but not in APP/E3 mice in agreement with RNA-seq data. Interestingly, we observed a significant decrease ofApoemRNA expression in plaque-associated microglia of APP/E4/Trem2(ko)vs APP/E4 mice. The absence of TREM2, worsened cognitive performance in APP transgenic mice but not their WT littermates. Gene expression analysis identifiedTrem2signature - a cluster of highly connected immune response genes, commonly downregulated as a result ofTrem2deletion in all genotypes including APP and WT littermates. Furthermore, we identified sets of genes that were affected in TREM2- and APOE isoform-dependent manner. Among them wereClec7aandCsf1rupregulated in APP/E4 vs APP/E3 mice, a result further validated by in situ hybridization analysis. In contrast,Tyrobpand several genes involved in the C1Q complement cascade had a higher expression level in APP/E3 versus their APP/E4 counterparts. Conclusions Our data demonstrate that lack ofTrem2differentially impacts the phenotype and brain transcriptome of APP mice expressing human APOE isoforms. The changes probably reflect the different effect of APOE isoforms on amyloid deposition.